Conversations With Prostate Cancer Experts

Category Archives: prostate cancer clinical trials

Dr. Fatima Karzai is the Director of the Prostate Cancer Clinic for the Genitourinary Branch at the National Cancer Institute. She’s keenly interested in developing novel strategies for harnessing the power of the immune system for hormonally driven cancers, particularly in advanced prostate cancer.

Prostatepedia spoke with her about a clinical trial she’s running that combines PARP inhibitors and a class of immunotherapeutic agents called PD-L1 inhibitors in men with advanced prostate cancer.

Why did you become a doctor? What is it about medicine that keeps you interested?

Dr. Fatima Karzai: I decided to become a doctor at a very young age. I’ve always wanted to help people. When I was younger, I thought that being a doctor was the best way to do that. I really enjoy patient interactions, so that’s why I’m a clinical researcher and I see patients on clinical trials. I find that it’s the most rewarding experience to be able to interact with patients. It’s always been a goal of mine to be able to help people in this manner. I think oncology was best suited for me to do so.

What are PARP inhibitors and PD-L1 inhibitors? How do they work, in which patients are they used, and how effective are they?

Dr. Karzai: PD-L1 inhibitors are members of a group of drugs called checkpoint inhibitors that have been developed for the treatment of cancer. PD-L1 is a protein that is present on the surface of cells. In cancer, PD-L1 on the tumor cells interacts with another protein on a person’s white blood cells, which are immune cells that help fight cancer. This PD-L1 protein prevents the immune system from attacking the tumor cells. A PD-L1 inhibitor blocks that ability of the tumor cell to suppress our immune system, which can help our immune system kill cancer cells. They’ve been successful in certain cancer types like lung cancer and bladder cancer.

PARP inhibitors are a type of targeted therapy. We all have DNA in our bodies; when it becomes damaged, our bodies know how to repair it. Many things can cause DNA damage: exposure to UV light, radiation, or substances in the environment. There is an enzyme in cells called PARP. PARP helps repair DNA when it becomes damaged. By blocking PARP in cancer cells, we can keep cancer cells from repairing their damaged DNA, which causes them to die. PARP inhibitors work very well in a subset of patients whose tumors harbor something called “DNA damage repair mutations.” These mutations can occur in the tumor itself or it could be something that a patient is born with. PARP inhibitors were initially studied in ovarian cancer and breast cancer. We’re starting to use them more in prostate cancer.

What is the rationale between combining the two agents for prostate cancer?

Dr. Karzai: We wanted to expand the use of PARP inhibitors. Like I mentioned before, right now they’re used in patients with these specific mutations. We’re trying to figure out if we’re able to get this class of drugs to work in patients without these mutations if we combine them with another drug. Historically, PD-L1 inhibitors have not been that successful in prostate cancer, so we decided to put these two drugs together to see if there is any additive or synergistic mechanism that could help patients with advanced prostate cancer.

What have the studies revealed about the combination?

Dr. Karzai: We are still accruing to the study. We’ve looked in-depth at the first 17 patients and seen deep and prolonged responses in men with castrate-resistant prostate cancer with the combination, in men who have these germline or somatic DNA damage repair abnormalities. We’re now adding additional patients to the study to better define the activity and to help us evaluate the biology more.

You said you’re still looking for more patients?

Dr. Karzai: Correct.

Tell us a little bit more about eligibility criteria and who men can contact if they think they’re a fit.

Dr. Karzai: We are looking for patients with advanced prostate cancer—i.e. the prostate cancer has gone outside the prostate and is in either the soft tissue, organs, and/ or bones. We would like to have these patients previously treated with either Zytiga (abiraterone) or Xtandi (enzalutamide). We think patients who have progressed on these two treatments might be more amenable to our combination. We allow previous chemotherapy, so if a patient has had Taxotere (docetaxel) or some other chemotherapy, they would be eligible. We are looking for patients who are still able to perform their activities of daily living and would be willing to participate in our trial and travel.

Some of our patients are local, but many come from across the United States. We even have some international patients.

You help defray the cost of travel for some of your clinical trial participants, don’t you?

Dr. Karzai: We do. Once a patient is on one of our protocols, then we reimburse flights in the United States. We also have a stipend for meals and hotels.

Any further thoughts on this particular combination or other combinations that you think may hold promise?

Dr. Karzai: Even though this type of immune therapy hasn’t been very successful thus far in prostate cancer, I still think that we need to do more studies and research to be able to find the subset of patients that it might work in. Immunotherapy is very exciting. We shouldn’t count it out in prostate cancer yet. The first vaccine that was FDA-approved in cancer was actually for prostate cancer. I think that the whole realm of immunotherapy is still open and could provide benefits for our patients. I am happy to see any patient for a consultation —those with newly diagnosed disease or those who are more advanced. We have clinical trials that span that spectrum of prostate cancer.

Dr. James Gulley: I think this has to go back to my high school biology teacher. His name was Vernon McNeilus. He was a retired orthopedic surgeon who just found a way to instill inspiration and that sense of curiosity about life. He drove us to really be excited and interested in science and in biology in particular. I had decided that I wanted to do something in science or medicine, but there was no way that I was going to go spend all that time to become a doctor. I’d been in school long enough. One of my friends decided he was going to go into medicine. I said if he can do it, I can certainly do it.

Then it actually evolved even further than that because during my stint in college I got the opportunity to do a summer research program. I decided I liked research, so I applied to MD/PhD programs and got accepted into two. I decided to go to Loma Linda.

What is it about medicine that keeps you interested?

Dr. Gulley: I think the thing that really drives me is how fascinating it is to understand how things work. I’ve always been fascinated in what makes things work. As a little boy I would take things apart trying to figure out what made them work and then put them back together again. If something was broken in the house, my mom would just give it to me and I’d tinker with it and get it to work again.

To me, the ultimate machine is the human body and one serious puzzle is to figure out ways to bring back health from sickness. Not just a puzzle for curiosity’s sake, but because of the effect that cancer can have on families, to uncover ways to effectively treat cancer. I think it’s truly something that I have seen patients who were close to death who have had remarkable and prolonged clinical responses. That, to me, begs the question that if we can do it for some people, then why can’t we do it for all people? That is what I am passionate about.

Are there any patients you’ve had over the years whose cases changed how you see your own role or the art of medicine?

Dr. Gulley: I’ve had several patients that have been exceptional responders; that really has changed how I view things. One of my more recent exceptional responses from this past year is a retired army surgeon who has advanced metastatic castrate resistant prostate cancer. I have been treating him since 2005. He was initially treated with radical prostatectomy. It turned out that he had a high Gleason disease. He had radiation therapy, but he had recurrence of his disease, unfortunately. He was treated with hormonal therapy, with chemotherapy, with Provenge (sipuleucel-T), and Xtandi (enzalutamide).

He came to me last year having had multiple therapies including other experimental immunotherapies. He was clearly not doing well. His PSA was going up very quickly with a doubling time of less than a month. His symptoms were getting substantially worse. He articulated to me that even going to church every week was becoming difficult: one week he was able to sing the songs and the next week he was too tired to sing. Then the next week he was almost too tired to stand up.

We were able to enroll him in a study combining a vaccine with checkpoint inhibition. When we gave him that combination, his PSA dropped dramatically. It has now gone to undetectable. His lesion in his bladder, which was causing local symptoms so that he had to have a chronic indwelling Foley catheter, shrunk away. When we biopsied it there was no evidence of tumor there. He has some lesions that are seen on bone scan, but I’m not sure if that represents viable tumor or not.

He is now over a year out from when he started treatment. His energy level hasn’t been better since before he was diagnosed. He is out doing everything he wants to do. To me that is amazing. It is amazing we can see responses like that.

From a scientific standpoint, of course, I was stunned to see this and wondered could he have micro-satellite instability that leads to lots of mutations. It turned out that he had micro-satellite instability in his cancer, suggesting that the immune system was able to see his cancer much more readily, so all we need to do is allow those immune system cells to be functional with the Opdivo (nivolumab).

We also had one other patient that didn’t have micro-satellite instability with this combination who also had a really nice 90% or so drop in his PSA. It’s not undetectable, but he hasn’t had the immune checkpoint inhibition for well over a year now. He’s just on vaccine alone because he had some bleeding in his urine from the checkpoint inhibitor. To me, having responses like that changes my outlook. It says the immune system, even in patients with prostate cancer, can be harnessed to attack the tumor. We just have to figure out ways that we can make this more applicable to all patients.

Dr. Channing Paller, an Assistant Professor of Oncology at Johns Hopkins University School of Medicine, focuses on translational research and clinical trials of developmental therapeutics in prostate and other solid tumors.

She is keenly interested in the rigorous evaluation of natural products in cancer treatment.

Dr. Channing Paller: One of my interests is studying natural products that people take as dietary supplements. We don’t know whether they work or whether they cause harm, so I test them. Several of my clinical trials study these compounds rigorously in a placebo-controlled fashion, as we would with any cancer treatment.

I knew about a recent randomized study of high dose intravenous ascorbic acid (vitamin C) in ovarian cancer patients, which showed that ascorbic acid treatment combined with standard chemotherapy reduced toxicities from the chemotherapy and also trended towards improved overall survival. Vitamin C enabled the patients to receive more cycles of chemotherapy, and that was associated with longer overall survival.

In response to the findings in ovarian cancer, the Prostate Cancer Foundation sent out a request for proposals for early stage research on vitamin C’s role in treating prostate cancer. We decided to initiate a large (60 patient) placebo-controlled trial with co-primary endpoints of quality of life and cancer response to the combination of intravenous (IV) vitamin C and chemotherapy. We are extremely grateful to the Marcus Foundation for supporting the trial.

We chose Taxotere (docetaxel) because it was first line and an easy place to start to answer the question. Jevtana (cabazitaxel) would have worked just as well.

What can patients expect to happen during the trial?

Dr. Paller:We are conducting a randomized placebo-controlled Phase II trial of standard-of-care Taxotere (docetaxel) for metastatic castrate resistant prostate cancer with either ascorbic acid or placebo, which is electrolytes and hydration, given twice a week in between the cycles of chemotherapy every three weeks. Some people say that this is too big a commitment, so they get to take breaks if needed. They can miss a session or two here or there. They can even take two weeks’ break, if needed. We’re trying to help people live better, not chain them to the clinic.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles, has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with him about collaborations between healthcare and tech industries for prostate cancer.

Have you had any particular patients or cases that changed how you view your role as a doctor or how you practice medicine?

Dr. Paul Nguyen: Several years after treating him, I heard from a patient who recounted for me what it was like to meet with me when he had first been diagnosed with recurrent disease. He said he’d had a lot of uncertainty and anxiety about his future. He said that the way I spoke with him had changed it entirely for him. He said I had a plan for him, knew exactly what we were going to need to do, and that we were going to do it.

I didn’t do anything particularly different in that encounter than I normally do, but hearing that made me realize how patients really hang on our every word, our every facial expression, our every cadence, and the emotion that we project when we speak. This made me so aware and conscious of making sure that, at all times, in every encounter, I have that combination of being sure about what I need to do and maintaining hope and optimism in every part of our discussions.

That was a good learning cycle for me. I hadn’t thought of it that way when I was with a patient. You just don’t think that every intonation, every gesture has such a huge impact. But it does. That was a very valuable learning experience for me that has really shaped how I think about every patient encounter before I walk into the room.

What are your current research projects? Which are you most excited about?

Dr. Nguyen: I have spent my entire career using information from the medical record about patients’ health status and tumor characteristics to figure out which men should get hormone therapy and for how long. Now, I’m incredibly excited about the opportunity to unleash the power of genetic testing of tumors. This will help us understand, on a genetic and molecular level, which patients should be given hormone therapy and for exactly how long. This will be a lot more precise than the clinical information by itself. I’m working with Dr. Felix Feng and others, which has been a wonderful collaboration.

How do you see evolving technologies impacting prostate cancer research? Dr. Nguyen: Technology gives us opportunities to do the kinds of studies we never dreamed possible, which is amazing.

I’ll give you an example. Dr. Feng and I are about to take prostate cancer samples from biopsy tissues taken 25 years ago from men who had cancer, samples stored without a clear purpose in mind. I give a huge amount of credit to the people who designed these studies in the early 1990s. They had no way to analyze this tissue, but they knew that someday, this tissue would be important to humanity. There wasn’t a specific test that they were storing these samples for, but they knew some kind of technology could decode what was going on in those tumors, to study how the tumors work, and who should get which treatment.

I feel so fortunate to come along 25 years later, when we do have the technology to analyze this tissue, and research it. This is the research I’m about to do now, which would never have been possible without new technologies.

Do you see technology impacting how we design clinical trials from the get-go?

Dr. Nguyen: Absolutely, because now people are designing trials with technology. There’s a trial being led by Dr. Feng from UCSF and Dr. Dan Spratt at the University of Michigan that incorporates genetic technology.

All the patients are tested upfront with this new technology to help decide which arm the patient goes into, which is really cool. This new scientific technology is being worked into clinical trial design.

Which innovations or technologies have the biggest impact?

Dr. Nguyen: There are two kinds of impacts. One is the ability to do large-scale genomic studies for a relatively low price. That has been a game-changer because it used to be so expensive to sequence the DNA of patients, but now you can approximate that rather cheaply and then do studies on thousands of patients. This way, we can pick up very small signals, which are very valuable.

The other invaluable impact is the ability to detect very minute amounts of tumor in the blood, very tiny traces that can tell us a lot.

In the circulating tumor cell?

Dr. Nguyen: Exactly.

Do you think artificial intelligence will play a role?

Dr. Nguyen: For sure. I’ve spent most of my career working on simple, clinical data. You can see the patterns of simple data yourself by doing simple statistical analyses. But now, the patterns are much more complex. Instead of five datapoints, you might have two million datapoints per patient. So we need AI. We need sophisticated machine learning to help us discern some kind of pattern out of that huge amount of data, to help us make sense of it.

Are there any specific collaborations, other than the ones we’ve already discussed, that you think look promising?

Dr. Nguyen: We’re seeing a lot more collaborations across specialties and disciplines to get research done. So much of what we’re seeing now is team science whereas people used to do studies with their own group.

Now, if you look at a paper, it’s not just one group or one discipline. At each institution, it’s five disciplines, and then you might have ten institutions on a paper, each contributing something different because that’s just what it takes now.

Every group has its own, little special expertise that gets put together to get a big paper or a big trial done. That’s what has really exploded. We’ve all recognized that, in order to get good science done, we have to team up.

Is just it easier to collaborate with people now via email and sharing of data? Or is there something about the way cancer research has been funded that has fostered that collaboration?

Dr. Nguyen: Yes. Those factors definitely contribute. It is definitely easier to share data now with the internet. Efforts to fund team science have definitely led teams to be created that might not have been created organically before.

There’s something fundamental about the increasing use of technology in studies and trials where only certain groups have this kind of technology expertise. You might have one group that knows a lot about the technology and another group that has a large number of patients and ideas. And you have to reach outside of your little sphere in order to get these kinds of exciting studies done.

It seems like before everything was pretty much siloed: you had tech, you had healthcare, and then, within healthcare, you had prostate cancer versus pancreatic cancer versus breast cancer. But now, the walls are coming down between those silos, with things like increased genetic testing. Would you say that’s true?

Dr. Nguyen: Absolutely. For example, some of the cool studies done in prostate cancer genetics were modeled on similar research done in breast cancer genetics several years before. Breast cancer had the Oncotype study, and then prostate cancer developed the Oncotype test many years later. We’ve seen molecular subtypes of breast cancer (luminal A, luminal B, and basal), and now there’s a study led by Dr. Feng suggesting that you’ve got similar kinds of subtypes in prostate cancer. We have to be knowledgeable about other fields. You can’t just be in your own silo now.

Last week, I spoke with engineers at University of Pennsylvania who are working with microchip-based technologies and machine learning to increase liquid biopsy’s usefulness in pancreatic cancer. They said this allows them to process much more data than they could before. They hope this has potential in other cancers. I know that’s more along the lines of diagnostics than what you’re doing, but do you have any thoughts about that?

Dr. Nguyen: We are all trying to take those same kinds of approaches with the folks who do machine learning. We need them desperately now because we’ve got so much data, and we just can’t figure it out on our own.

How did you find out you had prostate cancer? How did that journey begin?

Tim B: In 2005, I had a rising PSA. Every year or so, we did a PSA test because the urologist was concerned about my rising PSA. I was over the limit for my age. I had three biopsies. Eventually, they found out I had cancer, which was a Gleason score of 7, a 3+4. Not a whole lot of cores were involved, which was good. I thought that if I changed my diet, I would be able to do active surveillance, so I did. That lasted about nine months. My PSA kept going up.

Finally, I had a radical prostatectomy in 2013 and I had clean margins. There was nothing outside the prostate as far as they could tell. I continued on my healthy diet. I’m into heavy exercise; skiing, swimming, walking, and playing golf.

Unfortunately, about six months later, I had a PSA of 0.03, which meant there was still some cancer left. I was hoping it would die, but it didn’t. My PSA was going up slowly. I waited around until it got to 0.5. Then at 0.5, I decided to do something and talked to my urologist. He told me I should go on hormone therapy and salvage radiation. What a terrible name!

I agree. It’s a terrible name.

Tim B: I really didn’t want to do the standard of care. So, I asked if I could join a clinical trial. I was open. If something were out there that could help me and the world, that’s a pretty cool thing. He told me about a urologist down at UCSF, Dr. Eric Small. I went to the website—and I’m sure other men would experience this— they’ve got all these clinical trials, but I couldn’t figure out which trials I fit into. It’s very confusing. I live in Reno, so my wife and I drove down to San Francisco, and we met with Dr. Small. There was one trial he thought might work, but he needed to see me every month in San Francisco. I said, “If we can do something and get rid of the cancer in some way, I’m willing to drive from Reno to San Francisco once a month to meet with you.” (Over 200 miles away).

Dr Small explained there were three segments to the trial: either I’d get only experimental drug, only hormone therapy, or a combination of the two. He said I could back out of the trial if I found it wasn’t the right thing for me. I was hesitant. The only two classifications I was really interested in were the experimental drug by itself and the experimental drug with hormone therapy. He understood, but encouraged me to sign up. I signed all the papers. It turned out I got only the experimental drug, which was perfect. That began my journey.

Because experimental drugs are experimental, they don’t know the right dosage. They have ideas. They know how it works. But in Phase II, you’re a guinea pig. You’ve got to assume you’re a guinea pig, and some men won’t like that. I figured somebody’s got to do it. It’s a valuable thing for the rest of the men in the world.

My dosage was four pills a day. My PSA was up to 2.0 and the cancer was growing very fast. The doubling time was about two or three months when I started taking the drug. And the drug started working right away. After the first month, my PSA dropped down to 0.03. By the second month, it dropped to undetectable. I thought it was great!

During the third month, I got hives. The hives were so bad, I couldn’t get out of bed. I was the first one in the trial that had gotten hives and rash because I was the first to get the new formulation unknown to me. A number of other men experienced the hives later because, in the midst of the trial, they changed the formulation. But it was only two weeks of agony and pain for me, as they eventually cut back the dosage by a quarter. I also found out, fortunately, that

Southwest Airlines had a really inexpensive flight down to Oakland. I could take the BART around to San Francisco. The flight was $49 each way, which was a no-brainer. It’s less than I spent on driving. I could actually make a roundtrip to San Francisco in one day, and so it became much less expensive.

The whole time I was taking the drug, my PSA stayed undetectable. But then, unfortunately, the trial was over in August 2017. I had to go off the drug. My PSA started going up again, doubling every three or four months. My PSA is now up to over 1.2, and I’ve had to go to the standard of care. I’m on hormone therapy, and I start radiation in May. I avoided the standard of care for two years, which to me was worthwhile. And, I helped get the drug through the FDA.

I loved the drug. I would love it if the FDA approved the drug. Right now, it is approved for a more serious metastasized cancer. But I’m hoping that it becomes available to all men because that would really improve their quality of life.

What would you say to other men who are thinking about a clinical trial?

Tim B: Because this is an experiment, it’s going to be a bumpy road, and you’ve got to be ready for a couple of bumps along the way. Hopefully, you don’t get a rash or anything negative. The nice thing was I knew what drug I was getting.

We decided that we didn’t want to take a chance of being a placebo group, although trials are generally set up so that you can back out. So, if your PSA starts going up, you can get out. I would say, get a good doctor who you can communicate with. I thought Dr. Small was a great doctor to talk and work with. His team was very helpful. Those were benefits. I couldn’t have known beforehand, but the fact that they’re a teaching university that does research helped a lot.

Don’t expect that the trial will solve all your problems. Obviously, here I am two years later going down the path I didn’t want to go down, but I can’t find any other trials that fit me. If there were another trial, I know Dr. Small would tell me about it.

Your urologist becomes another advocate. You need to build your network of people. That’s how I look at Dr. Small, as part of my support network.

You’re a member of Silicon Valley Prostate Cancer Education and Support Group through El Camino Hospital, right?

Tim B: I was. I’m now a member of the Renown prostate support group here in Reno, now. But I stay on the Silicon Valley email list because they send out informative emails, and no matter where you are, you can’t get enough information. I love the fact that new developments are going on to protect men.

Are clinical trials a subject matter that comes up in your Reno support group? Is it something that men are talking about?

Tim B: In my group, they do not presently, but when I was living in Silicon Valley, we did. I’ve done lots of the experimental trials (not FDA approved). I had an inter-rectal MRI once when I was in the Valley. I also had a PSMA PET scan, which showed that I have presently got lesions in my prostate bed.

I know I’ve got cancer, and I’ve got to do something about it. More trials are performed nationwide near teaching universities. Trials are not for everybody, but if you’re willing, the developments are happening so fast that you can’t afford not to be thinking about clinical trials as an opportunity.

That’s great.

Tim B: I’m very excited about the future. I hope that something like Erleada (apalutamide), which was ARN-509, becomes a standard of care. I think that these drugs have the potential to help a lot of men.

Ms. Marie Vastola is a Clinical Research Assistant in Radiation Oncology at Dana-Farber/Brigham and Women’s Cancer Center. She works on Dana-Farber-led and international clinical trials that accrue men with multiple stages of prostate cancer. She is an author on six research articles focusing on prostate cancer and has presented her research at a national conference.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles and has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with them about how eligibility requirements for prostate cancer clinical trials may unfairly exclude African American men.

How have black men been underrepresented historically in prostate clinical trials? What are some of the prevailing theories or ideas about why that might be?

Dr. Nguyen: It’s multifactorial, and that was something that our research aimed to get at. Because of the historical experiences like the Tuskegee experiment, some African- Americans may have been more leery of engaging in clinical trials. Because trials require certain costs and extra time away from work, this can be more difficult on certain populations. Or it could be from the doctor side. Some doctors may not be as willing to engage African-American patients to enroll them on trials. There are multiple factors, so it’s hard to know exactly what is the main driver.

Ms. Vastola: We have patients come from long distances to Dana-Farber, and they do that because they know that Dana-Farber is a good place for them to get treated. Many patients, especially ones who travel long distances, either have connections in the medical field and that’s how they found out about this, or they’re highly educated and they have the resources to look into research and potential treatments themselves. These are tools that only people who are a little more privileged have.

Why did you zero in on eligibility criteria? What were you looking at?

Ms. Vastola: Actually, a patient is what started this research project. I had been screening an African-American patient for one of our open trials, and filling out the paperwork to determine if he was eligible. Most of this paperwork is related to the cancer, to make sure that patients have the type of cancer that we’re studying. But other sections of the checklist establish that the patient is otherwise healthy. We wouldn’t want to give an experimental treatment to a patient who wasn’t healthy for their sake and for the research’s integrity. He didn’t meet the criteria for one of those health checks.

One of the ways we determine that a patient is otherwise healthy is to look at their immune function, and his white blood cell count was too low. I hadn’t seen that before, and we ran his blood test again. His medical oncologist said the patient had benign ethnic neutropenia, which I had never heard of it until then. Because of that he couldn’t go on the trial that we had. It wasn’t a trial that we were running out of this hospital, but we talked to the sponsors. And as with many big trials, they don’t allow exceptions, no matter what.

He didn’t get the opportunity to be on a trial that was designed for men just like him, and that was really frustrating. Everyone involved with his treatment was frustrated with that, and so we looked into if that could be happening to other men. We also looked at creatinine. It’s well known in the medical field that black patients have a higher serum creatinine, and so you have to use a special formula that accounts for race when you’re looking at their kidney function. We looked at benign ethnic neutropenia because that’s what started it, and it was something that people seemed unaware of.

Dr. Nguyen: In a research group, the ideas usually come from the lab principal investigator (PI), and then the junior people carry it out. In this case, Marie actually came up with this idea herself because of a patient experience that she had, seeing an African-American patient not be able to get on one of our trials. It’s what led to this Journal of the American Medical Association Oncology paper, which is impressive.

That is. What did you look at?

Ms. Vastola: We wanted to know how often this happens. Was this a fluke, or does this happen to other African-American men? The best way to find out was to look at the eligibility criteria of other trials. Every trial records when people don’t meet the criteria. They don’t often record why though, so we couldn’t just look at the internal records of our trials. The website clinicaltrials.gov lists all trials available to patients in the United States and also a lot of international trials, and it usually lists the eligibility criteria. Not all the trials go into detailed criteria, but many do. We went through 401 trials that had endpoints that we thought meant that they had the potential to reach large audiences and change practice. We looked at all of them and pulled the eligibility criteria to see how many of them had this white blood cell criterion.

We expected some would have it. We did not expect that almost 50% of trials would have either of these two criteria. We were also surprised that the serum creatinine criterion was so common that a quarter of the trials have it.

People are aware of this, and they know to calculate kidney function accounting for race. A lot of trials would use serum creatinine, which is just the blood test, but then they would also say that if a patient meets formula criteria (based on race), then they’re okay, which is what we want to see. Not all trials do that, and that’s the issue. Every single lab result you look at that measures creatinine says at the bottom that if the patient is African-American, apply this formula. But over 25% of these trials weren’t including that formula.

What else did you find?

Ms. Vastola: Those were the two criteria that we looked at. We also broke it down by year, size of the trial, the phase, and toxicity of the therapy. We were glad to see that, over time, people are using the serum creatinine eligibility criteria less and less, which may mean that more people are aware of it. That’s not the case for the white blood cell criterion though.

Dr. Nguyen: We looked only at trials that have survival as an endpoint, so these are trials looking to make people live longer. We think it’s especially important that all patients have equal access to these kinds of trials. There are a few consequences of not having African-Americans on these trials. Patients who go on trials can sometimes get access to new drugs, so it’s a problem if African-American patients aren’t getting on trials. We also don’t get to learn enough about whether certain drugs perform particularly well in African-Americans, and so we don’t get to learn about the specific benefits or lack of benefit of certain agents for African-American patients. We wind up extrapolating from the larger patient pool, which probably works most of the time, but perhaps there’s something special that we can learn from having African-American patients on trials so that we could find better cures that can be tailored for African-American patients.

Ms. Vastola: Exactly. Not having access to these clinical trials hurts the individual because they don’t have access to treatment that could potentially help them. But the lack of access also hurts the whole population.

It also skews your results, so that what you’re learning about isn’t really prostate cancer in all men, just prostate cancer in a subset of men.

Ms. Vastola: Exactly.

What do you hope this will mean for clinical trial design and eligibility recruitments?

Ms. Vastola: We presented this research letter at the Prostate Cancer Symposium of the American Society for Clinical Oncology in poster form. We got a lot of feedback from academic investigators, people who devote their lives to this. Their papers define the field. They said they’d never thought of this, and that some didn’t know benign ethnic neutropenia existed. This section of the eligibility criteria—the part that defines whether a patient is healthy—is just carried over from trial to trial because it’s so standard. It’s not something people think about when they design trials because it’s so standard.

It’s textbook. We hope that, as more people understand this, they will consider it when they design their trials.

Dr. Nguyen: We were guilty of it in our own trials, and that’s how this all came about. We just used standard entry criteria copied over from previous studies. We were surprised to learn that this could disproportionally disadvantage African-American patients from being able to enroll in our trials. Given all the barriers that African-American patients face in getting on clinical trials in the first place, the last thing that we need is yet another barrier.

Dr. Ravi Madan (@Dr_RaviMadan), the clinical director of the National Cancer Institute’s Genitourinary Malignancies Branch, focuses on immune stimulating therapies. In particular, he’s interested in how we can combine these approaches with other therapies to improve patients’ lives.

Prostatepedia spoke with him about clinical trials for prostate cancer patients.

Why has it been difficult for doctors to enroll patients in clinical trials?

Dr. Ravi Madan: The reasons vary from case to case. Sometimes physicians don’t mention relevant trials at the right time for patients (when they’re making treatment decisions). Sometimes patients don’t want to go through the process of enrollment because of the perception that it delays their care and that delay will somehow impact their outcome. There is also personal preference. Some patients really don’t like the uncertainty of a clinical trial—uncertainty in terms of what their treatment will be if there’s a randomization or uncertainty about the outcome.

Trials should be discussed with patients when they’re making a decision to change therapies. While enrollment does take time, it’s usually only a few weeks, and for the most part, that doesn’t impact the patient’s outcomes or overall course. Ultimately, patients need to have a risks/benefits conversation with their doctor to determine if a clinical trial fits into the personal treatment strategy that they’ve developed with their doctor and their family.

Perhaps many people assume clinical trials aren’t really available until you have advanced disease, but that’s not really true is it? There are trials available at all stages along the journey.

Dr. Madan: Correct. Trials exist in all stages of the disease. The ones that often get the most notoriety, either on television or in the news, are the ones for late-stage patients. But for example, here at the National Cancer Institute (NCI), we have trials for every stage of prostate cancer, from patients who are newly diagnosed to early recurrence to non-metastatic, and then ultimately, late-stage disease.

Why would someone want to join a trial? Just to gain access to a treatment he may not otherwise have access to?

Dr. Madan: Sometimes you get access to treatments earlier than they may be available to the general public. People should understand that clinical trials often involve the standard of care they would get anyway plus an experimental agent.

There is an altruism component to a lot of this as well. It never ceases to amaze me, but when I deal with the patients here at the NCI, so many of them tell me: “If this helps me, that’s great, but I just want to help someone else later on.” It’s not like everybody has to have that reason, but it’s remarkable how many do. So, the reasons are variable. Sometimes it’s because there aren’t other options, but sometimes it’s because it adds options or adds cards to the playing deck, if you will, and sometimes it’s just pure altruism.

I guess that’s especially true in earlier-stage diseases, where you don’t necessarily need experimental treatment or access to something that you wouldn’t otherwise get access to, such as those on active surveillance.

Dr. Madan: Correct. We have patients in studies who just have rising PSAs where we’re trying to evaluate the potential of immunotherapy in that setting, but the alternative therapy is just really observation for a lot of those patients. For them, the trial is an opportunity to do something when the standard of care might be to do nothing.

What about the concept of the placebo? I’ve heard patients say they’re afraid of getting a placebo, which could make their cancer worse. Is that still a part of the clinical trial world?

Dr. Madan: It is part of the clinical trial world. Many trials require a placebo because in order to scientifically answer a question, there may have to be a group of patients who are untreated. In those circumstances, the protocol (a document that is often over a hundred pages) is designed to protect those patients. Whenever patients are on placebos, there are very strict guidelines about how they’re watched and the parameters used to remove them if there’s evidence that their cancer is getting worse. In some cases, they have scans very frequently. They’re not left unminded, and it’s usually for a short time.

But many trials don’t involve placebos. We conduct trials to see if we can take a standard therapy that’s in use and add something to it to make it better, and this is especially true in this new age of immunotherapy.

In that process, everybody will get the standard therapy, and some of the patients will get the experimental therapy in addition.

They’re not just getting a placebo, and then left unmoored.

Dr. Madan: Right. There are very strict criteria about how patients are monitored so that, if there is evidence that the cancer is getting worse—regardless if it’s standard therapy or placebo—then they move onto something else. In many trials with placebos, oftentimes the physicians don’t even know what the patients are getting, so the physicians often treat them all like they’re getting the placebo because that’s really the safest thing from a patient’s standpoint.

That’s interesting.

Dr. Madan: We need to monitor placebo patients closely in case they are getting nothing, and we need to move on to something else. But if a trial involves placebo, patients should be comfortable with that and comfortable with the relationship with their doctor who’s going to help them make these decisions. Otherwise, it creates a lot of stress, whether in the initial process with the randomization or while they’re on the study.

What about the financial end of trials? Do patients have to pay to participate in clinical trials—for the therapy itself, the procedure, the scan, or more? Or are the costs just travel expenses and time away from work?

Dr. Madan: Generally speaking, patients don’t pay the price for the drug treatments on a clinical trial. Sometimes trials are billed so the insurance company will cover standard costs that would be covered anyway. But for the most part, the patients do not incur the cost of the clinical trial. Costs are borne out by the companies or research bodies that conduct the trials.

Here at the National Cancer Institute (NCI), we are able to conduct trials that are completely free of charge to the patients. And in addition to that, because we are a government entity designed to really benefit the entire country, once patients are enrolled in our trials, we are able to fly them in from different parts of the country.

We can incur the travel costs for patients who travel from anywhere in the United States. That’s part of our mission here: to bring the benefits of this institution to everyone in the country.

Wow! So your clinical trial patients only have to pay for their hotel and time away from work?

Dr. Madan: Correct. And most patients qualify for a subsidy toward their hotel.

Dr. Madan: Yes. It’s an unusual circumstance. It allows our institution to address diseases that may not affect many patients within one geographical area. It’s a unique opportunity to conduct studies on rare diseases, but we also use it for studies in more common diseases.

You don’t want to just study prostate cancer in men in the metropolitan D.C. area, right?

Dr. Madan: Correct. For example,

I have studies with medullary thryoid cancer, which is a very rare disease. But we’re able to get people from across the country and do it in a way that no other institution can because our catchment area is the entire country.

How can men find out about clinical trials? My impression is that the usual path is that their doctor brings it up, or perhaps they hear about it in a support group, but what are some ways that men can find out about trials? Just by visiting clinicaltrials.gov?

Dr. Madan: I would actually recommend https://www.cancer.gov/about-cancer/treatment/clinical-trials/search because clinicaltrials.gov is more for clinicians. One of the greatest features of cancer.gov is you can search by zip code or city, and it tells you trials within 25, 50, 100 miles, or whatever you like. But either website has a great patient-based resources. I encourage patients to bring up clinical trial options with their doctors and get their doctors’ thoughts on what they find.

Patient support groups are another excellent resource. Depending on the cancer, there are also online support groups that are more prevalent and will probably become more so. Over about a third of our patients are self-referred from around the country, and not just referred by doctors, so it’s common for patients to advocate for themselves in this manner.

I was under the impression that if, for example, a man found one of your trials on clinicaltrials.gov and thought he was a perfect fit, he had to go back through his doctor to get involved in the trial. Is that true? Or can he contact you or the researcher directly?

Dr. Madan: Yes; he or she can contact the researcher directly. I get some calls directly from patients saying they saw this on the internet. We also have a clinical trials contact, so no, they don’t have to go through their doctor. I often encourage patients to speak to their doctor just to get an impartial perspective or additional perspective.

Also, patients and doctors have very good relationships usually, and it’s important to get a second opinion before you embark on the clinical trial journey.

But certainly they can contact us directly, and they very frequently do.

When studies are finally completed and published in academic journals, are patients informed, or do they have access to those results?

Dr. Madan: There’s not often a direct mechanism by which patients are informed about the results of the trial. But often, through the course of a study, patients will ask about the experiences so far. We’ll certainly fill them in, and then we have had patients call us up for results. We certainly publish the results and can share them, but there’s not a direct mechanism.

Interesting. There probably should be.

Dr. Madan: That’s an interesting idea. It’s possible some institutions have that. I’m not aware of any at this time.

But patients can always ask their contact directly, right?

Dr. Madan: Yes.

What else should patients know about joining clinical trials?

Dr. Madan: Clinical trials can be an important part of each patient’s individual treatment strategy. Especially for patients with cancer, it’s important for them to develop these strategies in conversations with their doctor and their families, and to develop that strategy based on personal preferences.

Clinical trials are a way to get additional treatment options over time, options beside the standard options that are generally available. Being on a trial requires a little additional time, and there is potential for side effects. If there’s a randomization process, patients should be comfortable with that, no matter what they get.

As the patients who come to NCI from all over, consider local trials and those around the country. Sometimes travel is not optimal, but we’ve had patients come in from as far away as Hawaii and Alaska. Take advantage of the opportunity if you can. The pace of cancer research today is remarkable, especially in immunotherapy, which is one of the biggest focuses here at NCI.

All of us should remember that none of these advances would have happened without remarkable patients who decided to enroll in clinical trials. I consider it an honor to be able to work with the types of people who enroll in trials here at NCI and around the country. It’s really an extraordinary and humbling experience for me.